This application is for a supplement to the program project, Alzheimer's Disease Neuroimaging Initiative (ADNI). Although the research participants in this study will be extensively investigated, no mechanism exists for the systematic pathological validation of the clinical diagnoses made during life. Neuropathology is the gold standard for defining age-related brain changes and the diagnosis of dementias. Therefore, neuropathology is essential in order to validate the clinical assessments of ADNI participants during life. A centralized core is required to ensure uniformity and reliability of neuropathological assessment of tissues from multiple sites (Alzheimer's Disease Research Centers (ADRCs and ADCs, n=29; and non-ADRC/ADC sites, n=30) which use diverse processing, staining, and immunohistochemical procedures. In addition, participants who come to autopsy during the study period and beyond will be an invaluable resource for clinicopathological studies and will facilitate the aims of the biomarker studies of ADNI. To achieve these goals, the ADNI-Neuropathology Core (ADNI-NPC) will: 1. Assist sites in obtaining provisional consent for autopsy from ADNI participating centers; 2. Provide central, uniform neuropathologic diagnoses to validate clinical assessment and facilitate clinicopathological correlations, including determining the relationship between the molecular neuropathology, structural, and functional changes, including Pittsburgh Compound-B (PIB), in early Alzheimer's disease; 3. Maintain a state-of-the-art brain tissue resource to advance collaborative research, and to facilitate ADNI's biomarker studies headed by John Trojanowski, Center for Neurodegenerative Disease Research, University of Pennsylvania, PA; 4. Interact with ADNI components, including the ADNI Coordinating Center, in order to support ADNI's research objectives. This supplement will focus on undertaking a neuropathological assessment of all cases recruited to ADNI who come to autopsy in the grant period of this project. Clinical, neuropsychological, and neuroimaging data obtained from ADNI will be available for correlation with the earliest changes in Alzheimer's disease (AD), mild cognitive impairment (MCI), normal aging, and other dementing diseases identified after neuropathological assessment. These studies will help us to assess the probability and rate that AD will progress within the brain. The harvesting of frozen brain tissue from the cases will facilitate the biomarkers study. Biochemical methods will be used to investigate changes in protein solubility which may offer early and novel targets for therapeutic intervention. [unreadable] [unreadable] [unreadable]